Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Abstract

Aims/hypothesis. Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism. Methods. Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated. Results. Non-esterified fatty acids decreased glucosestimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucosestimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2. Conclusion/interpretation. In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression. [Diabetologia (2004) 47:463-469]

Peroxisome Proliferator–Activated Receptor α Improves Pancreatic Adaptation to Insulin Resistance in Obese Mice and Reduces Lipotoxicity in Human Islets

“…As previously reported in human islets (24,25), incubation with fatty acids for 48 h resulted in triglyceride accumulation (P Ͻ 0.001) and apoptosis of islets (P Ͻ 0.001) (Fig. 7D and E).…”

Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells

“…Preparation of islets, cell culture, secretion assays, immunofluorescence, determination of cAMP and CREactivation Rat islets or human donor islets were obtained and cultured as described [18,19] and approved by the ethics committee. For calcium imaging, rat islet cells were seeded on polylysine-coated glass coverslips (6,000/coverslip, 25 mm diameter) and precultured for 4 days at 11 mmol/l glucose before transfection with lipofectamine.…”

Tissue-specific effects of leptin administration on the abundance of mitochondrial proteins during neonatal development

“…Exposure of rat islets to elevated plasma NEFA concentration, which has long-term (inhibitory) and short-term (stimulatory) effects on glucose-stimulated insulin secretion, did increase UCP2 abundance (Lameloise et al 2001). This contrasts with our negative association between mean plasma NEFA and pancreatic UCP2 following leptin administration, suggesting a decrease in UCP2 may allow the pancreatic -cells to resist the detrimental effects of high NEFA exposure (Dubois et al 2004, Joseph et al 2004. Increased NEFA metabolism leads to an increase in energy flux through the electron transport chain, which can lead to enhanced production of reactive oxygen species in -cells (Carlsson et al 1999, Barbu et al 2002.…”